EP3669870A1 - Utilisation de carnosol pour augmenter la synthèse de protéines musculaires - Google Patents

Utilisation de carnosol pour augmenter la synthèse de protéines musculaires Download PDF

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Publication number
EP3669870A1
EP3669870A1 EP18306811.3A EP18306811A EP3669870A1 EP 3669870 A1 EP3669870 A1 EP 3669870A1 EP 18306811 A EP18306811 A EP 18306811A EP 3669870 A1 EP3669870 A1 EP 3669870A1
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European Patent Office
Prior art keywords
carnosol
subject
composition
muscle
protein synthesis
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EP18306811.3A
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German (de)
English (en)
Inventor
Gilles Carnac
Nathalie Saint
Sylvie Morel
Sylvie Rapior
Manon Vitou
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Universite Paul-Valery Montpellier 3
Centre National de la Recherche Scientifique CNRS
Universite de Montpellier I
Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Montpellier
Institut de Recherche pour le Developpement IRD
Ecole Pratique des Hautes Etudes SAS
Original Assignee
Universite Paul-Valery Montpellier 3
Centre National de la Recherche Scientifique CNRS
Universite de Montpellier I
Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Montpellier
Institut de Recherche pour le Developpement IRD
Ecole Pratique des Hautes Etudes SAS
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Application filed by Universite Paul-Valery Montpellier 3, Centre National de la Recherche Scientifique CNRS, Universite de Montpellier I, Institut National de la Sante et de la Recherche Medicale INSERM, Universite de Montpellier, Institut de Recherche pour le Developpement IRD, Ecole Pratique des Hautes Etudes SAS filed Critical Universite Paul-Valery Montpellier 3
Priority to EP18306811.3A priority Critical patent/EP3669870A1/fr
Priority to US17/415,084 priority patent/US20220062228A1/en
Priority to EP19828734.4A priority patent/EP3897619B1/fr
Priority to CN201980083332.1A priority patent/CN113853201A/zh
Priority to PCT/EP2019/086235 priority patent/WO2020127681A1/fr
Priority to ES19828734T priority patent/ES2934476T3/es
Priority to CA3123346A priority patent/CA3123346A1/fr
Publication of EP3669870A1 publication Critical patent/EP3669870A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents

Definitions

  • the present invention relates to the increase of muscle protein synthesis, the reduction of the muscle protein degradation, the prevention and/or the treatment of pathological or non pathological loss of muscular mass in a subject.
  • the skeletal muscles represent around 45% of the body mass. Due to its ability to generate the strength, the muscle is responsible of mobility, breathing and posture.
  • the skeletal muscles play also a key role as a regulator of metabolism by using a large quantity of glucose and lipids, in particular during exercise.
  • Many pathological (cancer, diabetes%) or non pathological (sedentary lifestyle, bed rest, immobilization, stay in space%) conditions lead to a loss of muscle mass thereby reducing functional capacities and life expectancy.
  • carnosol has a hypertrophic effect on muscle. They have shown that carnosol stimulates the synthesis of protein in muscle cells while it inhibits the degradation of proteins.
  • a subject of the present invention is therefore the use of carnosol or of a composition comprising carnosol for increasing muscle protein synthesis in a subject.
  • the present invention also relates to the use of carnosol or of a composition comprising carnosol for reducing the muscle protein degradation in a subject.
  • Carnosol (CAS 5957-80-2) is an ortho -diphenolic dipterpene having the following structure:
  • Carnosol has been first isolated in 1942 from the plant Salvia carnosa (purple sage). Subsequently, carnosol has been extracted from many other plant species including rosemary. Carnosol possesses a range of therapeutic effects such as anti-cancer, anti-inflammatory, and anti-oxidant activities ( Kashyap D. et al., Mechanistic insight into carnosol-mediated pharmacological effects: Recent trends and advancements. Life Sci. 2017 Jan 15;169:27-36 ). However, until the discovery of the inventors, no hypertrophic effect of carnosol on muscle had been shown.
  • the carnosol for use according the present invention may be carnosol extracted from a plant extract, in particular extracted from rosemary, or synthetic carnosol.
  • An extract of rosemary leaves which comprises carnosol may be used for the same applications as the applications of the composition comprising carnosol according to the invention.
  • composition comprising carnosol
  • composition comprising carnosol may be a food supplement or a medicament
  • the composition comprising carnosol comprises an effective amount, preferably a therapeutically effective amount of active ingredient i. e. the carnosol together with an excipient.
  • an "effective amount” as used herein refers to that amount which is sufficient to provide a hypertrophic effect on muscle in the subject to whom it is administered.
  • Muscle hypertrophic effect refers to an increase in the volume and/or the muscle mass. This increase in the volume and/or muscle mass may go along with a modification in muscle morphology or not.
  • the effect of the composition according to the invention can be readily verified by various assays, using appropriate animal models or muscle cells culture models.
  • the effective dose is determined and adjusted depending on factors such as the composition used, the route of administration, the physical characteristics of the individual under consideration such as sex, age and weight, concurrent medication, and other factors, that those skilled in the medical arts will recognize. For example, it is well known within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, typically from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the composition comprising carnosol comprises at least 0.1% w/w, preferably at least 0.5% w/w, more preferably at least 1%, 5% or 10% w/w of carnosol.
  • compositions according to the invention are formulated for parenteral, transdermal, oral, rectal, intrapulmonary, subcutaneous, sublingual, topical or intranasal administration.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • compositions according to the invention are formulated for oral or topical administration, more preferably oral administration.
  • composition comprising carnosol may also comprise another active ingredient in addition to carnosol for example a compound selected from the group consisting of antioxidant, amino acid source and vitamin D.
  • antioxidant any antioxidant may be used, preferably the antioxidant is selected from the group consisting of polyphenols, vitamins, carotenoids, trace elements and combinations thereof.
  • the vitamins may for example be vitamin E (tocopherol), vitamin A (retinol or beta-carotene) or vitamin C (ascorbic acid).
  • the trace element is preferably selenium.
  • antioxidant fruit extracts or dried fruits are pears, apples, raisins, grapes, figs, cranberries, blueberries, blackberries, raspberries, strawberries, blackcurrants, cherries, plums, oranges, mango, and/or pomegranates.
  • Antioxidants may be used as purified compounds or partially purified compounds.
  • the composition comprising carnosol also comprises vitamin D.
  • composition comprising carnosol also comprises an amino acid source.
  • the amino acid source may be amino acids in free form or it may be peptides and/or proteins.
  • the protein source may be dairy, animal or vegetable proteins.
  • the amino acid source is a protein selected from the group consisting of whey protein, casein protein, pea protein, soy protein, wheat protein, corn protein, or rice protein, proteins from legumes, cereals and grains in general or combinations thereof.
  • the protein may also be selected from nuts and seeds.
  • the amino acid source is preferably a whey protein.
  • the composition comprising carnosol does not comprise a compound selected from the group consisting of ursolic acid, vitamin D, an amino acid source and eicosapentaenoic acid.
  • An object of the present invention is a method for increasing muscle proteins synthesis and/or for reducing the muscle protein degradation in a subject in need thereof comprising a step of administering to said subject an effective amount of carnosol or of a composition comprising carnosol.
  • the carnosol may be used in many applications such as applications involving the prevention and/or the loss of muscle mass, in particular loss of skeletal muscle mass.
  • carnosol may be used in therapeutic applications for example in order to treat and/or prevent muscle atrophy, in particular sarcopenia; in non therapeutic applications for example in a subject who has lost or have a risk of loss its muscle mass due to an immobilization or a stay in space but also in sportspersons in order to increase their performance.
  • carnosol may be used in farming in order to increase the muscle mass of livestock animals.
  • the subject to whom is administered the carnosol or the composition comprising carnosol according to the various embodiments of the invention may be a human or a non human animal.
  • the subject may be an elderly or a young subject.
  • an elderly subject refers to a human over 60 years old and a young subject refers to a human under 30 years old.
  • the subject is an elderly subject.
  • the subject is selected in the group consisting of a subject having a sedentary lifestyle, a subject at bed rest or having been at bedrest, an immobilized subject, an undernourished subject, a malnourished subject and an astronaut.
  • the subject is a domestic animal, preferably livestock or poultry.
  • carnosol according to the invention may be accompanied by physical exercise.
  • An object of the invention is carnosol or a composition comprising carnosol for use in the prevention and/or the treatment of muscle atrophy in a subject.
  • the present invention also relates to a method for the prevention and/or the treatment of muscle atrophy in a subject in need thereof comprising the step of administering to said subject an effective amount of carnosol or of a composition comprising carnosol.
  • the present invention also relates to the use of carnosol or of a composition comprising carnosol in the manufacture of a medicament for the prevention and/or the treatment of muscle atrophy and/or muscular dystrophy, preferably muscle atrophy.
  • Muscular dystrophy may be selected from the group consisting of Duchenne muscular dystrophy, Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy.
  • Muscle atrophy may be caused by many reasons. For example, it may result from several diseases, such as cancer, AIDS, congestive heart failure, COPD (chronic obstructive pulmonary disease), renal failure, trauma, sepsis, severe burns, mental disease such as anorexia, neuronal disease, cachexia, obesity and drug-related iatrogenia.
  • diseases such as cancer, AIDS, congestive heart failure, COPD (chronic obstructive pulmonary disease), renal failure, trauma, sepsis, severe burns, mental disease such as anorexia, neuronal disease, cachexia, obesity and drug-related iatrogenia.
  • carnosol or the composition comprising carnosol according to the invention is for use in the prevention and/or the treatment of sarcopenia in a subject.
  • the muscle atrophy may be of different grades, such as severe muscle atrophy as in extreme frailty elderly persons. These elderly persons will have difficulty in carry on every day activities and taking care of them self. Muscle atrophy, but of a less severe degree will allow some movement and some muscle activity, but insufficient to sustain the complete muscle tissue.
  • the loss of muscle mass may also result from disuse or insufficient use of the respective muscle. For example, it may result from lack of physical activity, such as from immobilization or hip-fracture recovery. Muscle atrophy may also be caused by insufficient or inappropriate nutrition or starvation.
  • the present invention also relates to the use of carnosol or of a composition comprising carnosol for preventing and/or treating loss of muscle mass and/or for increasing muscle mass in a subject.
  • the present invention relates to a method for preventing and/or treating loss of muscle mass and/or for increasing muscle mass in a subject in need thereof comprising a step of administering to said subject an effective amount of carnosol or of a composition comprising carnosol.
  • the subject may be selected from the group consisting of a subject having a sedentary lifestyle, a subject at bed rest or having been at bedrest, an immobilized subject, an undernourished subject, a malnourished subject and an astronaut.
  • the subject may also be a sportsperson.
  • carnosol or composition comprising carnosol allows sportspersons to increase their performance.
  • the carnosol may also have an application in farming.
  • Another object of the invention is the use of carnosol for increasing the muscle mass in livestock or poultry.
  • the present invention also relates to a method for increasing muscle mass of livestock animal comprising the step of administrating to said animal a feed comprising carnosol.
  • the inventors In order to assay the hypertrophic effect on muscle of compounds from vegetal extracts, the inventors have designed a culture cell model of human skeletal muscle satellite cells.
  • the skeletal muscle satellite cells are able to proliferate and to differentiate ex vivo. When cultured in a growth factors rich medium, the skeletal muscle satellite cells proliferate in the form of myoblasts.
  • the myoblasts morphologically differentiate by fusing thereby producing long multinucleated cells (myotubes or myofibers) which express muscular protein.
  • Myotubes are able to respond to hypertrophic and atrophic signals by modulating the balance between the protein synthesis (hypertrophy) or the protein degradation (atrophy) ( El Haddad M. et al., Cell Mol Life Sci. 2017 May;74(10):1923-1936 ).
  • the recovered skeletal muscle satellite cells used in the culture cell model by the inventors were recovered from a muscular biopsy of young and elderly subjects.
  • the satellite cells can be easily recovered from a muscle biopsy and cultured ex vivo in dishes where they proliferate as myoblasts and differentiate into myotubes.
  • the biopsy is treated according to an experimental protocol described and validated by us for human skeletal muscle from quadriceps (Kitzmann et al., 2006; El Haddad et al 2017).
  • the biopsy is cut into a fragment of 1 mm 3 and placed in a culture dish treated with type 1 collagen.
  • the explants are trapped inside in a thin layer of Matrigel (BD Matrigel Matrix, BD Biosciences) in 35 mm-collagen coated Petri dishes with growth media (DMEM/F12, supplemented with 10 % fetal bovine serum, 0.1% Ultroser G, 1 ng/ml basic FGF, and 10 microg/mL gentamicin).
  • growth media DMEM/F12, supplemented with 10 % fetal bovine serum, 0.1% Ultroser G, 1 ng/ml basic FGF, and 10 microg/mL gentamicin.
  • muscle differentiation is induced by growing confluent myoblasts in differentiation medium depleted of growth factors. At confluence, myoblasts start to differentiate and differentiation can be evidenced 1) morphologically (after 2 to 4 days), as the fusion of myoblasts generates long giant multinucleated cells (named myotubes) and 2) biochemically, as myotubes express proteins required for muscle contraction. Differentiation is assessed by immunofluorescence using the antibodies against Troponin T and Myogenin, two markers of muscle differentiation. The differentiation status is also confirmed by precisely measuring the expression of three differentiation markers (Myogenin, Sarcomeric Actin and Caveolin by RT-qPCR). Expression of RPLP0 is also quantified as internal control.
  • myoblasts are seeded at 10 5 cells/dish onto 35 mm collagen-coated dishes and cultured in growth medium (DMEM/F12, supplemented with 10% fetal bovine serum, 0.1% Ultroser G, 1 ng/ml basic FGF, and 10 microg/ml gentamicin).
  • growth medium DMEM/F12, supplemented with 10% fetal bovine serum, 0.1% Ultroser G, 1 ng/ml basic FGF, and 10 microg/ml gentamicin.
  • Myogenic differentiation of confluent cells was induced after 3 days by changing to DMEM containing 5% FBS (differentiation medium). Cells were kept in differentiation medium for 3 to 4 days.
  • troponin T a protein of the cytoskeleton which is exclusively expressed by myotubes
  • the area of myotubes is measured using the Image J software. If the area increases the compound has a hypertrophic activity and if the area decreases the compound has an atrophic activity.
  • the hypertrophic activity of hydroalcoholic extract of rosemary leaves was tested in the cell model disclosed above.
  • the skeletal muscle satellite cells came from young people (aged under 30).
  • a hydroalcoholic extract of rosemary leaves exerts a hypertrophic activity on myotubes when it is at a concentration of 20 ⁇ g/ml in the culture medium.
  • Wild rosemary was harvested in north of Jardin (France). The dried leaves were crushed and an extraction was carried out directly. 150 g of crushed rosemary leaves were put in obscurity at room temperature in a mix comprising 900 g of ethanol absolute and 450 g of distilled water. The mix was manually agitated every 24 hours. After 7 days maceration, the extract was filtrated. Evaporation was made on dry reduced pression. 69 g of hydroalcoholic extract of rosemary leaves called hereinafter RL was obtained.
  • fraction M also shown a hypertrophic activity but weak compared to fraction C.
  • fraction C consists of pure carnosol.
  • the hypertrophic compound from the extract of rosemary leaves is the carnosol.
  • the hypertrophic activity of commercially available carnosol was assayed ( figure 3 ).
  • the commercially available carnosol shows the same hypertrophic activity as the fraction C purified from rosemary leaves.
  • Carnosol shows a hypertrophic activity from 0.5 ⁇ g/ml (1-2 ⁇ M)
  • the hypertrophic activity of carnosol was assayed at various concentrations (0.25 ⁇ g/ml, 0.5 ⁇ g/ml, 1 ⁇ g/ml, 2.5 ⁇ g/ml and 5 ⁇ g/ml). The results are shown in figure 4 .
  • the carnosol exhibits a hypertrophic activity from 0.5 ⁇ g/ml (i. e. from 1 to 2 ⁇ M) in the cell culture model.
  • the hypertrophic activity of carnosol was compared to other antioxidant compounds.
  • carnosol has a significant hypertrophic activity.
  • the hypertrophic activity of carnosol goes beyond its antioxidant activity (carnosol: 2 ⁇ g/ml; carnosic acid: 2 ⁇ g/ml; rosmarinic acid: 2 ⁇ g/ml; ursolic acid: 2 ⁇ g/ml; vitamin C: 50 ⁇ g/ml).
  • the hypertrophic activity of carnosol and carnosic acid was compared. Whereas carnosic acid has a structure very close from the one of carnosol, the hypertrophic activity of carnosol is significantly higher than the one of carnosic acid. This suggests that the hypertrophic activity of carnosol is specific ( figure 6 ).
  • the culture cell model disclosed above was used with skeletal muscle satellite cells recovered from elderly subjects (subject 1 and subject 2) in order to assay the hypertrophic activity of carnosol on myotube cells from elderly subject.
  • the carnosol has also a hypertrophic activity on myotube cells of elderly subjects (carnosol: 2 ⁇ g/ml).
  • the muscular hypertrophic activity of carnosol may result from a global increase of the synthesis of proteins.
  • the culture cell model disclosed above was stimulated with carnosol. Then, 30 minutes before recovering the protein from the cells, the cells were treated with puromycin. The puromycin is incorporated in the neo-synthetized proteins. Then, a western blot was carried out with anti-puromycin antibodies in order to show the translation rate of the mRNA in the living cells ( Schmidt et al., SUnSET, a nonradioactive method to monitor protein synthesis. Nat Methods. 2009;6:275-277 ) (see figure 8 ).
  • the expression of the MuRF1 and MAFbx mRNA is higher in conditions inducing skeletal muscle atrophy (inactivity, denervation, malnutrition, glucocorticoids treatment, oxidative stress, and inflammation).
  • the experiments on mice wherein the expression of MuRF1 or MAFbx was inactivated suggest that MuRF1 would be a better candidate than MAFbx to develop targeted drugs in order to inhibit its expression and thus treat muscular atrophy. Indeed, deleting MuRF1 prevents muscular atrophy in more physiological or physiopathological conditions than the MAFbx deletion.
  • the muscular mass which is preserved in response to the MuRF1 deletion seems to be more functional with the strength proportional to the quantity of muscle ( Bodine and Baehr, Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx/atrogin-1; Am J Physiol Endocrinol Metab. 2014 Sep 15;307(6):E469-84 ).

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EP18306811.3A 2018-12-21 2018-12-21 Utilisation de carnosol pour augmenter la synthèse de protéines musculaires Withdrawn EP3669870A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP18306811.3A EP3669870A1 (fr) 2018-12-21 2018-12-21 Utilisation de carnosol pour augmenter la synthèse de protéines musculaires
US17/415,084 US20220062228A1 (en) 2018-12-21 2019-12-19 Use of carnosol for increasing muscle protein synthesis
EP19828734.4A EP3897619B1 (fr) 2018-12-21 2019-12-19 Utilisation de carnosol pour augmenter la synthèse de protéines musculaires
CN201980083332.1A CN113853201A (zh) 2018-12-21 2019-12-19 鼠尾草酚在增加肌蛋白合成的用途
PCT/EP2019/086235 WO2020127681A1 (fr) 2018-12-21 2019-12-19 Utilisation de carnosol pour augmenter la synthèse de protéines musculaires
ES19828734T ES2934476T3 (es) 2018-12-21 2019-12-19 Utilización de carnosol para el aumento de la síntesis de proteínas musculares
CA3123346A CA3123346A1 (fr) 2018-12-21 2019-12-19 Utilisation de carnosol pour augmenter la synthese de proteines musculaires

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WO2006101663A1 (fr) * 2005-03-23 2006-09-28 Mccleary Edward L Composition et procede permettant de moduler la physiologie de l'ion d'hydrogene
WO2009106125A1 (fr) * 2008-02-25 2009-09-03 Nestec S.A. Polyphénols destinés au traitement des troubles du cartilage
JP5884112B2 (ja) * 2014-01-23 2016-03-15 有限会社 坂本薬草園 筋肉増強剤

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US20220062228A1 (en) 2022-03-03
CN113853201A (zh) 2021-12-28
EP3897619B1 (fr) 2022-11-23
EP3897619A1 (fr) 2021-10-27
ES2934476T3 (es) 2023-02-22
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